The nerve tissue located at the center of the retina of the eye is called as a macula. The macula includes most of phtoreceptor cells responding to light stimuli; and the appearances of objects are focused at the center of the macula. Therefore, the macular plays an essential role in maintaining eyesight. Age-related macular degeneration (AMD) is a chronic disease characterized by the degenerations in the retinal pigment epithelium and Bruch's membrane in the macular as well as the choroidal capillary. Anatomically, the sensory retina is located in front of the retinal pigment epithelium. The nutrition, support, recycling, and treatment of wastes of the sensory retina depend on the retinal pigment epithelium. Bruch's membrane having a five-layered structure is sandwiched between the choroid and the retinal pigment epithelium. The innermost layer is a basal membrane of the retinal pigment epithelium; and the outermost layer is a basal membrane of the choroidal capillary. That is, the macular degeneration is a degenerative disease occurred in the complex of the retinal pigment epithelium, Bruch's membrane, and the choroidal capillary.
This disease, which occurs primarily in the ages over 50 years old, is the main cause of blindness in the population of more than 60 years old in the Western countries; and the trend thereof is also increasing in Korea. Although the cause of age-related macular degeneration is not still elucidated, the risk factors include age (especially, sharp increase is shown after the age of 75 years old), smoking (most notable environmental risk factor), high blood pressure, obesity, genetic cause, excessive UV exposure, low blood concentration of antioxidant, and the like.
In the macular degeneration, there are two types, i.e., dry (non-exudative) macular degeneration and wet (exudative) macular degeneration. The dry macular degeneration (dry AMD, non-exudative AMD, or non-neovascular AMD) is associated with the waste formation of yellow deposits, known as drusen, under the retina. The large formation of drusen causes disturbing the blood flow to the retina, especially to the macular, which leads to obscure vision, thereby bring about visual impairment. Although the dry macular degeneration does not cause a sudden loss of vision, it may be developed to a wet macular degeneration. Under the retina, there are the choroid containing a set of vessels buried within the fibrous tissue and the pigment epithelium covering the choroid layer. The wet macular degeneration (wet AMD, exudative AMD, or neovascular AMD) is associated with the angiogenesis from the choroid area under the retina. The burst of these weak neovessels causes hemorrhage and exudation, which leads to degeneration in the macula area of the retina, thereby bring about visual impairment. Because the wet macular degeneration is developed very rapidly, it is known that vision can be deteriorated in several weeks; or that loss of vision can be caused between 2 month and 3 years.
As a therapy for macular degeneration, a photodynamic therapy (PDT) and an injection therapy of antibody against angiogenic growth factor are currently being used. The photodynamic therapy is a method which comprises injecting a photosensitizer, Visudyne, through the blood vessels, followed by irradiation of the eye with a specific laser reactive only to the photosensitizer at the time when the photosensitizer arrives at neovessels of the retina, so as to selectively destroy the neovessels. However, the photodynamic therapy causes many recurrent cases after the treatment, which requires repetitive treatments. And also, there is a drawback that the repetitive treatments causes damage of the retina itself. The antibody injection therapy is a method injecting directly into the retina an anti-VEGF antibody which inhibits the formation and proliferation of neovessels through selectively binding to the vascular endothelial growth factor (VEGF) critical to the formation and progression of neovessels. As a protein drug used in the antibody injection therapy, there are Lucentis and Avastin. Lucentis has been approved by the FDA as a therapeutic agent of wet macular degeneration. Although Avastin is approved to treat cancer, it is being clinically used to treat wet AMD.
The antibody injection therapy has some drawbacks: for example, it requires high therapeutic cost, local administration (especially direct administration into the eye), and repeated injections. Therefore, in terms of patients' drug compliance, therapeutic cost, etc., there is a need for developing an (non-injectable) eye drop formulation based on a low-molecular weight synthetic compound.